Potential New Weapon against Lou Gehrig's Disease

A protein that helps combat stress on cells caused by environmental influences like rising ambient temperatures appears to block the onset of amyotrophic lateral sclerosis (ALS), at least in a mouse model of the neurodegenerative illness.

Commonly known as Lou Gehrig's disease (after the famed New York Yankee slugger who succumbed to it in 1941 at age 37), ALS is a poorly understood, incurable disorder characterized by the degeneration of motor neurons (nerve cells that control voluntary motion). Signals from these cells to the muscles weaken in victims, resulting in atrophy, speech disruptions and, eventually, total loss of control over movement. About one in every 50,000 people in the U.S. is diagnosed with the debilitating condition annually; it typically strikes between the ages of 40 and 60 and leads to respiratory failure and death within five years of onset.

ALS ravages two distinct populations of motor neurons—one in the brain, the other in the spinal cord. The endings of the spinal cord cells interface with neighboring muscle cells, normally signaling muscles to contract or relax to create motion. But researchers at Wake Forest University Baptist Medical Center in Winston?Salem, N.C., found that ALS-affected neurons undergo a process known as "denervation" that severs the connection.

The scientists report in The Journal of Neuroscience, however, that they were able to preserve these neuromuscular links in mice genetically engineered to develop ALS by injecting heat protein 70 (Hsp70) into their backs, thus delaying the onset of the disease. This protein is secreted in large quantities by neurons in response to stressors. Hsp70 maintains proper nerve cell function by binding to the neurons and chaperoning proper protein folding inside. Previous models of ALS demonstrated that neurons sustain damage when stressed, because Hsp70 levels do not rise to corresponding levels.

Genetic analyses have shown that 90 percent of ALS cases are caused by spontaneous mutations that are not inherited. In the 10 percent of inherited cases, a common mutation occurs in the gene superoxide dismutase 1 (SOD1), which is the gene that the Wake Forest team altered in its mouse model. Fifty days after the mice were born, one group was injected three times a week with Hsp70 and another received Riluzole, the only drug approved by the Food and Drug Administration to combat ALS.

The mice that received Riluzole lived, on average, one day longer than those that received no treatment. In contrast, those that received Hsp70 lived 10 days longer. At the neuromuscular juncture, where muscle and nerve cells meet, the researchers noted the Hsp70 mice had 20 percent more neurons in communication with muscle cells than the untreated control group.

"When we injected the protein, it tended to work more peripherally at the neuromuscular junction, and perhaps that is the difference," Milligan says. "We were assuming that it would go into the spinal cord and have an effect on the motor neuron cell body. … It suggests optimal treatment should be looking both at the periphery and at the spinal cord."

Milligan and her team now will attempt to uncover the mechanism by which the Hsp70 influx aids the so-called innervation of neurons and muscle cells. They will also explore therapeutic cocktails that include Hsp70 to target the neuromuscular juncture and at least one other component to attend nerve cell bodies.

In addition, they plan to replicate the results of this study and test new drug combinations against the disease in various animal models in which other genes are changed. "I think testing reagents in multiple [disease] models may give a better indicator of what would be effective in the patient population," Milligan says.